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pharmacovigilance
risk–benefi t ratio of marketed drugs at the individual level (ie, the choice of the most suitable treatment for a given patient) and at Author
the population level (ie, maintenance or removal of a drug from the Paolo Biffi gnandi, EU Vigilance, UK, Germany and Italy market, informing prescribers of its potential risks, etc). This process relies heavily on the reporting and analysis of ADRs. Unfortunately, there is no consensus on ADR defi nitions. Consensus has been reached in the industry and the regulatory arena with the efforts of ICH (International Conference of Harmonisation) and CIOMS Key words
(Council for International Organizations of Medical Sciences). Pharmacovigilance, Drug safety, Drug monitoring and reporting, Signal However, there is no agreement on the meaning of an ADR between healthcare professionals and patients, and the emotional involvement of patients and sometimes the physician in defi ning any drug-related Abstract
effect creates diffi culties in many cases. This article will discuss some general considerations on the complexity Moreover, even the unique focus on ADRs which encompasses of pharmacovigilance: the real scope of pharmacovigilance, the many all pharmacovigilance activities may be misleading. Not every ‘adverse’ actors involved in this process, the peculiarity of drug monitoring and side-effect (ie, ‘unwanted’ in respect of the approved indication or the issue of feedback to healthcare professionals from collection and the desire of the physician and/or the patient) is necessarily ‘adverse’ collation of safety data of medicines. in the broader perspective: the case of the antithrombotic action of aspirin at a population level is an example of an ADR which became a useful novel indication for this drug. So in addition to assessing a Introduction
drug’s safety over and above what is known at the time of a marketing Modern drug safety, in the sense of widespread, routine, post- authorisation, pharmacovigilance can also be a major tool to better marketing surveillance of drugs for new safety issues, came into understand the actions of human medicines on a larger scale, in real being following the unpredicted teratogenic outcomes from the life settings and with varied conditions of use. use of thalidomide in the mid-1960s. During the intervening years, pharmacovigilance has been defi ned in many ways, sometimes The many actors involved
with divergent concepts and aims (see Box), but the recent As outlined by the WHO Foundation Collaborating Centre for ‘pharmaceutical package’ issued by the European Commission International Drug Monitoring,2 drug products are not like other products in December 20081 gives a concise yet comprehensive defi nition, by virtue of their heavy dependence on a ‘learned intermediary’ for the describing the pharmacovigilance system as the supervision and prescription and dispensing of the product between the manufacturer monitoring of adverse drug reactions (ADRs). and the end users, at least in countries with heavily regulated healthcare. Technical details about the activities inherent to In such countries there can be as many as four such intermediaries, pharmacovigilance will not be discussed here, since they are the including the prescriber/dispenser; the healthcare maintenance focus of many articles in this issue and in future issues of Regulatory authority (which issues general management plans for patients); and Rapporteur. However, some general considerations will be briefl y the regulatory authority (which decides on restrictions and availability mentioned to introduce the complexity of the process: the real of individual products). Each of these ‘learned intermediaries’ makes scope of pharmacovigilance, the many actors involved, the peculiarity decisions about the benefi ts and risks of medicines, although in none of drug monitoring and the issue of feedback from collection and of these decisions is there complete transparency for the end user. collation of safety data of medicines to the fi nal users.
Moreover, the interests and responsibilities of each intermediary may be in confl ict at times. For no other range of products is the technical The real scope of pharmacovigilance
complexity so great, the breadth of use universal, the impact so In general, pharmacovigilance is a multidisciplinary issue: basic and personal, and the responsibility for successful use so dispersed.
clinical pharmacology; clinical medicine; toxicology; epidemiology; and A single ADR may therefore arise from many different actions, (pharmaco)genetics are the major disciplines involved in this scientifi c some of them completely unrelated to the medicinal product process, which is coordinated by a stringent regulatory framework. involved. This dispersed chain of activities may pose serious problems The ultimate aim of pharmacovigilance is the optimisation of the when assessing the real value of an ADR. Regulatory Rapporteur – Vol 6, No 2, February 2009 get feedback on what I reported regarding my individual patient, the For no other range of products is the drug I prescribed, the conditions of its use. If a sound pharmacovigilance system is to be foreseen, then it should be able to answer these technical complexity so great, the breadth of questions. If not, it may only be a good exercise for regulatory bodies use universal, the impact so personal, and the without the active involvement of major stakeholders. responsibility for successful use so dispersed Conclusion
The complexity of pharmacovigilance is not only related to the
The peculiarity of drug monitoring
increasing regulatory requirements but also to the number of factors Safety of a medicinal product is generally evaluated during the involved. The regulatory framework, although greatly improved clinical development phase (Phase II-III). This means that a controlled compared with the past, is still not able to include all stakeholders. environment is used with stringent rules and criteria for the The communication and related legislative proposal of the EU selection of patients, drug administration and monitoring. Studies Commission on pharmacovigilance, issued on 10 December 2008, must comply with GCP and safety assessment is a scientifi c and is a major step forward which takes into account medication errors regulatory tool to generate sound and reproducible clinical data, but as well as the prevention and control of healthcare-associated the results seldom mimic the real world situation. When compiling infections. In essence, improvement in the protection of public health the proposed summary of product characteristics (SPC) required to will be achieved through clearer roles and responsibilities for key obtain a marketing authorisation, an applicant aims to collect all safety responsible parties (the learned intermediaries); more transparency information available at the time of the application, adding, where and communication on medicine’s safety issues (the feedback); and a possible, considerations about the specifi c drug class. Of course, this simplifi cation and rationalisation of the procedures in order to reach is somewhat incomplete information, although every attempt should a proactive and proportionate collection of high quality data (the real be made to get the best possible data. However, once authorised, a given medicinal product is then administered much of the time in a broader, more varied and less controlled manner. Clinical situations in real life medicine are much more complicated than in a clinical protocol. A practicing physician cannot generally apply such stringent The science and activities relating to the detection, assessment, criteria when treating a patient, and multitherapy is the rule rather understanding and prevention of adverse effects or any other than the exception. Here, pharmacovigilance has an immense value, being the only way to understand what reactions a drug may cause in the clinical setting. The question is, how can data from controlled studies be pooled with data coming from usage in the real world? Pharmacovigilance is all observational (nonrandomised) post- How can we overcome the historical reluctance of physicians to approval scientifi c and data gathering activities relating to the report ADRs? How can we understand if a given event is part of detection, assessment, and understanding of adverse events. This a poorly understood illness or caused by a given drug? No clearcut includes the use of pharmacoepidemiologic safety studies.
answer has been found so far by health authorities and healthcare professionals, and I doubt these issues will have an easy and practical ISPE – International Society of Pharmaco-Epidemiology (this is similar to the defi nition given by the US FDA) Feedback of pharmacovigilance reporting
The group of activities with the aim of the safe use of medicines. There is considerable effort to collect, collate and transmit ADRs These include legislative, offi cial, marketing authorisation holders’ across the current EU pharmacovigilance system. The main accent is and public health authorities’ activities.
on the correct transmission from the fi eld to the central repository (EudraVigilance), and the complexity of this activity is such that courses are mandatory to be a Qualifi ed Person for Pharmacovigilance (QPPV) Pharmacovigilance is the process and science of monitoring the in the EEA. However, to be able to transmit information is just part safety of medicines and taking action to reduce risks and increase of the problem, and very far from the solution. Even so-called and benefi ts from medicines. It is a key public health function.
expensive pharmacovigilance software is no more than a user-friendly European Commission – Enterprise and Industry tool to comply with regulations. Is this compliance all we really need? The answer is ‘No’. Having been a physician before becoming a regulatory professional, my dissatisfaction is enormous. As a physician reporting ADRs, I never References
received any feedback on what I reported, nor did I receive any http://ec.europa.eu/enterprise/pharmaceuticals/pharmacos/pharmpack_ suggestions on how to improve my clinical practice. Yes, there are safety bulletins, drug alerts on some websites, useful clinical articles sometimes, I R Edwards. ‘The future of pharmacovigilance: a personal view’, Eur J but what I really needed in my day-to-day work was very simple: to Clin Pharmacol, 64:173–181, 2008.
Regulatory Rapporteur – Vol 6, No 2, February 2009

Source: http://www.euvigilance.eu/www.euvigilance.eu/download/focus1_3.pdf